TY - JOUR
T1 - Structure of the Yersinia pestis FabV enoyl-ACP reductase and its interaction with two 2-pyridone inhibitors
AU - Hirschbeck, Maria W.
AU - Kuper, Jochen
AU - Lu, Hao
AU - Liu, Nina
AU - Neckles, Carla
AU - Shah, Sonam
AU - Wagner, Steffen
AU - Sotriffer, Christoph A.
AU - Tonge, Peter J.
AU - Kisker, Caroline
N1 - Funding Information:
This work was supported by the Rocky Mountain Regional Center for Excellence in Bioterrorism and Emerging Infectious Diseases through grant no. U54 AI065357 from the National Institutes of Health (P.J.T.; J.T. Belisle PI) and by the Deutsche Forschungsgemeinschaft (SFB 630 to C.K. and C.A.S. and Forschungszentrum FZ82 to C.K.). We thank the staff of beamlines 14.1 at BESSY II, Berlin and ID29 at the ESRF, Grenoble for technical support. In addition, C.N. was supported by Chemistry-Biology Interface Training Program grant no. T32GM092714 from the National Institutes of Health.
PY - 2012/1/11
Y1 - 2012/1/11
N2 - The recently discovered FabV enoyl-ACP reductase, which catalyzes the last step of the bacterial fatty acid biosynthesis (FAS-II) pathway, is a promising but unexploited drug target against the reemerging pathogen Yersinia pestis. The structure of Y. pestis FabV in complex with its cofactor reveals that the enzyme features the common architecture of the short-chain dehydrogenase reductase superfamily, but contains additional structural elements that are mostly folded around the usually flexible substrate-binding loop, thereby stabilizing it in a very tight conformation that seals the active site. The structures of FabV in complex with NADH and two newly developed 2-pyridone inhibitors provide insights for the development of new lead compounds, and suggest a mechanism by which the substrate-binding loop opens to admit the inhibitor, a motion that could also be coupled to the interaction of FabV with the acyl-carrier protein substrate.
AB - The recently discovered FabV enoyl-ACP reductase, which catalyzes the last step of the bacterial fatty acid biosynthesis (FAS-II) pathway, is a promising but unexploited drug target against the reemerging pathogen Yersinia pestis. The structure of Y. pestis FabV in complex with its cofactor reveals that the enzyme features the common architecture of the short-chain dehydrogenase reductase superfamily, but contains additional structural elements that are mostly folded around the usually flexible substrate-binding loop, thereby stabilizing it in a very tight conformation that seals the active site. The structures of FabV in complex with NADH and two newly developed 2-pyridone inhibitors provide insights for the development of new lead compounds, and suggest a mechanism by which the substrate-binding loop opens to admit the inhibitor, a motion that could also be coupled to the interaction of FabV with the acyl-carrier protein substrate.
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U2 - 10.1016/j.str.2011.07.019
DO - 10.1016/j.str.2011.07.019
M3 - Article
C2 - 22244758
AN - SCOPUS:84855818674
SN - 0969-2126
VL - 20
SP - 89
EP - 100
JO - Structure
JF - Structure
IS - 1
ER -